Endocrine System

The endocrine system is composed of glands and their chemical messengers called hormones. The endocrine system is instrumental in regulating growth and development, tissue function, metabolism, and reproductive processes. Hormones affect nearly every cell in the body by traveling through the bloodstream and binding to specialized receptors. This article reviews the structure and function of the major endocrine glands and the most important characterized hormones. It also reviews the endocrinology of pregnancy and fetal development, and briefly discusses the endocrine system’s role in growth and stress. Lastly, it reviews disorders of the endocrine system most relevant for infants and children.

I Introduction

Endocrine systems function by regulating and integrating physiological processes to meet specific needs of the organism and facilitate adaptation to dynamic and chronic environmental changes or perturbations. Internally, hormone systems are constantly changing in response to environmental cues such as photoperiod, temperature, energetic demands, food and water availability, and reproductive status or season. Hormones are the chemical substances that are typically produced and released into circulation by specialized cells that are localized in small glands or organs. Because of their great potency and ability to broadly influence bodily functions, hormones are regulated by an exquisite set of negative and positive feedback loops that may link several organs. For the most part, endocrine systems in marine mammals follow the basic organization and chemical characteristics of other mammals. Nevertheless, it is intriguing to examine how these systems allow marine mammals to meet the peculiar challenges imposed by their environment. The following sections will review and highlight our current understanding of endocrine systems and how they respond to either natural or artificially manipulated environments to enhance our knowledge of hormone functions in marine mammals.

Endocrine Disruptors

Dysfunction of the endocrine system could be due to either hyperfunction (excessive hormone production or responses) or hypofunction (insufficient hormone production or responses). Environmental chemicals that have the potential to perturb the endocrine system are known as endocrine or, synonymously, hormone disruptors.

The term endocrine disruptors was first used by Theo Colborn and Peter Thomas in 1992. In 1996, the US Environmental Protection Agency (EPA) convened a panel called the Endocrine Disruptors Screening and Testing Advisory Committee to make recommendations to EPA concerning endocrine disruptors. The term ‘endocrine disruptors’ has been used interchangeably with hormonally active agents and endocrine modulators. As the term is used now, endocrine disruptors include any substance that affects the synthesis, secretion, transport, binding, action, inactivation, or elimination of natural hormones in the body.

Excessive amounts of hormones in circulation may be due to overproduction of hormones in the endocrine organs, rapid release of hormones from storage, decreased hormone metabolism, or altered rate of clearance and excretion of hormones. On the other hand, cell injury in hormone-producing tissues, inhibition of synthetic enzymes, and induction of metabolic enzymes are causes of hormone deficiency.

The Exposure Patterns of NMs

To define whether NMs are harmful to the endocrine system, we need to consider the exposure patterns of NMs, including exposure routes, dose, and duration. Indeed, the same NMs may have different effects on endocrine functions depending upon the exposure.

The entry route is a major factor which affects the endocrine-disrupting effects of NMs. For vertebrate animals, the exposure routes used in experiments include inhalation, oral entry (water or food), intraperitoneal injection, and intravenous injection (Hoet et al., 2004). Among them, intravenous injection results in greater uptake than other routes (Crain and Guillette, 2000). Inhaled or oral NMs can be partially eliminated while some can be absorbed into the bloodstream. Then they may be transported to organs including endocrine organs via circulation (Hoet et al., 2004). EDs can pass through the liver, wherein they are metabolically detoxificated (Crain and Guillette, 2000). Since it is difficult for NMs to enter the body by dermal exposure (Hoet et al., 2004), few studies explore the adverse effects on endocrine organs or their functions after dermal exposure of NMs.

For invertebrate animals, NMs are often added into the environment. For example, aquatic animals are exposed to NMs in the water and flies are cultured in molasses culture medium supplemented with NMs.

Due to different usage, different NMs enter the bodies with different efficiency via different routes. For example, CBNPs are mainly taken into the body through inhalation, for example, from laser printer emission or through dermal uptake from cosmetics (Schmid and Riediker, 2008), so it is more meaningful to investigate the adverse effects of these NPs exposed by inhalation, intratracheal instillation (Yoshida et al., 2010), or dermal uptake. However, there are few studies which compare the endocrine-disrupting effects of the same kind of NMs at the same dose by different routes.

Endocrine-disrupting effects of NMs are induced in a dose-dependent manner. Many studies investigate the endocrine-disrupting effects of NMs at different doses and subsequently determine the lowest effective dose (Gavello et al., 2013; Gosso et al., 2011; Kong et al., 2014; Philbrook et al., 2011; Pietroiusti et al., 2011). For example, SWCNTs (from 10 ng to 30 μg per mouse) were administered to female mice soon after implantation (postcoital day 5.5); 10 days later, animals were sacrificed, and uteri, placentas, and fetuses examined. The lowest effective dose inducing miscarriage and fetal malformation was 100 ng per mouse (Pietroiusti et al., 2011).

However, there is a study showing that a relatively low dose of NP-rich diesel exhaust (NR-DE) induced endocrine-disrupting effects, while high dose exposure did not (Ramdhan et al., 2009). NR-DE exposure at low (22.5 ± 0.2 nm in diameter, 15.4 ± 1.0 mg/m³ in mass weight, 2.27 × 10⁵ cm⁻³ in mean number concentration) and medium (26.1 ± 0.5 nm, 36.4 ± 1.2 mg/m³, 5.11 * 10⁵ cm⁻³) concentrations for 1 and 2 months (5 h/day, 5 days/week) significantly increased plasma testosterone in male Fischer 344 rats, whereas exposure to a high concentration (27.1 ± 0.5 nm, 168.8 ± 2.7 mg/m³, 1.36 * 10⁶ cm⁻³) did not (Ramdhan et al., 2009). The reason why relatively low doses, but not high doses of NR-DEs induced endocrine-disrupting effects remains unclear, although a partial explanation is that EDs can act through receptor-mediated mechanisms, which allows them to act at very low doses and in a nonlinear manner. The dose–response curves can take many different forms (Crain and Guillette, 2000). Furthermore, for some EDs, effects at low doses may not be predictive of effects at high doses because of different mechanisms of action (Crain and Guillette, 2000).

The duration of exposure is also an important factor. For example, treatment with CdSe@ZnS core–shell QDs or CdTe QDs induced difficulty in egg laying and damaged eggs after long-term exposure (16 days) at a dose of 200 nM in female C. elegans, while no adverse reproductive effects were observed after exposure for less than 3 days (Qu et al., 2011). Since endocrine responses are often long-lasting and have a long latency, the relative long-term exposure may be required to evaluate the effect. In addition, since endocrine responses are often long-term and slow, there may be a latency period before NM-triggered effects are manifested. The latency period may be very short, such as 24 h, but sometimes it could be relatively long, up to weeks. For example, after 14 nm CBNP injection via tail vein to pregnant mice on GD 7 and 14, daily sperm production was significantly decreased in male offsprings of maternal mice exposed to CBNPs at the age of 15 weeks, but not at the age of 5 or 10 weeks (Yoshida et al., 2010). However, another report found that just 24 h after intravenous injection of TiO₂NPs (diameters of 35 nm) or silica NPs (diameters of 70 nm) at the dose of 0.8 mg per mouse via tail vein into pregnant BALB/c mice (8–10 weeks) on two consecutive days, GD 16 and GD 17, mice treated with NPs had smaller uteri and smaller fetuses compared to the untreated controls (Yamashita et al., 2011).

Nevertheless, endocrine-disrupting effects may also be reversible. In a recent study, silica NPs were injected at the dose of 20 mg/kg via tail vein into male ICR mice every 3 days, 5 times over 13 days (Xu et al., 2014). The study showed that silica NPs caused damages to mitochondrial cristae and decreased the levels of ATP, resulting in oxidative stress in the testis by days 15 and 35. However, the damage was repaired by day 60. Further, DNA damage and the decreases in the quantity and quality of epididymal sperm were found by days 15 and 35, but these changes were recovered by day 60 (Xu et al., 2014).

The critical windows of susceptibility to NMs should be carefully considered. Some NMs can induce endocrine-disrupting effects in adult animals (Yoshida et al., 2010), but other NMs exert adverse effects in fetal or neonatal animals, and not in adults (Pietroiusti et al., 2011; Yamashita et al., 2011). Hence, when endocrine-disrupting effects of NMs are investigated, the timing of the exposure should be prudently considered.

Hypophysis (pituitary gland)

Hypophysis, together with the hypothalamus is considered to be the master organ of the endocrine system influencing all the endocrine functions of the body. It is composed of an anterior lobe (adenohypophysis) that derives from the ectoderm of the oropharynx (Rathke’s pouch) and the posterior lobe (neurohypophysis) that is developing from the neuroectoderm, and thus it is part of the central nervous system. The anterior lobe contains acidophilic and basophilic cells as well as cells with pale cytoplasm called chromophobes; these cells produce the tropic and non-tropic hormones regulating other endocrine and non-endocrine functions. Non-tropic hormones, the growth hormone (GH) and prolactin (PRL) directly stimulate target cells to induce effects; in contrast, tropic hormones target other endocrine glands, and they include the thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Acidophils populating the lateral wedge of the adenohypophysis produce GH and PRL (somatotropes and lactotropes, respectively), while basophils producing ACTH and TSH (corticotropes and thyrotropes, respectively) populate the central wedge. The basophilic gonadotropes produce LH and FSH and they are scattered over the lateral wings and the central wedge. Between the anterior and posterior lobes, the pars intermedia contains cystic, colloid-filled cavities as well as basophils and chromophobes. The posterior lobe contains non-myelinated axon bundles originating from the hypothalamic magnocellular system as well as dilated axon terminals (Herring bodies).

Mechanisms of Toxicity

Classes of chemicals known to be toxic for the adrenal cortex include short chain (three or four carbon) aliphatic compounds, lipidosis inducers, and amphiphilic compounds. It would also appear that hormones, especially exogenous steroids, have a direct effect on the adrenal cortex. The most potent aliphatic compounds are of three-carbon length with electronegative groups at both ends. These compounds frequently produce necrosis, particularly in the ZF and ZR. Examples include acrylonitrile, 3-aminopropionitrile, 3-bromopropionitrile, 1-butanethiol, and 1,4-butanedithiol. By comparison, lipidosis inducers can cause the accumulations (often coalescing) of neutral fats, which may be of sufficient quantity to cause a loss of organellar function and cellular destruction. The ZR and ZF appear to be the principal targets of xenobiotic chemicals. Examples of the compounds causing lipidosis include aminoglutethimide, amphenone, anilines, and imidazole antimycotic drugs. Biologically active cationic amphiphilic compounds tend to produce a generalized phospholipidosis that involves primarily the ZR and ZF. They cause microscopic and subcellular phospholipid-rich inclusions. These compounds affect the functional integrity of lysosomes, which appear ultrastructurally to be enlarged and filled with membranous lamellae or myelin figures. Examples of compounds known to induce these types of effect include chloroquine, triparanol, and chlorphentermine.

Another class of compounds that affects the adrenal cortex is certain hormones, particularly natural and synthetic steroids. Some of these steroid hormones (corticosteroids) may cause functional inactivity and morphological atrophy during prolonged exogenous use (Figure 20.19). Other steroid hormones (natural and synthetic estrogens and androgens) have been reported to cause proliferative lesions in the adrenal cortex of laboratory animals.

Figure 20.19. Adrenal of control dog (B) and adrenal of dog with cortical atrophy (A) following treatment with excessive topical corticosteroids. H&E stain.

Figure reproduced from Handbook of Toxicologic Pathology, third ed., W. M. Haschek, C. G. Rousseaux and M. A. Wallig, eds. (2013) Academic Press, Fig. 58.7, p. 2400, with permission.

The final class of compounds represents a miscellaneous group of chemicals that affect hydroxylation and other functions of mitochondrial and microsomal fractions (smooth endoplasmic reticulum). Examples of these compounds include o,p′-DDD and -alpha-(l,4-dioxido-3-methylquinoxalin-2-yl)-N-methylnitrone (DMNM). Additional compounds in this category cause their effects by means of CYP metabolism and the activation of toxic metabolites. An example is the activation of carbon tetrachloride, resulting in lipid peroxidation and covalent binding to cellular macromolecules of the adrenal cortex. For another example, aminoglutethimide downregulates the ACTH receptor, and inhibits CYP11A1 (cholesterol side chain cleavage) and CYP11B1 (CYP11β/18), which is the terminal enzyme in cortisol synthesis.

Most chemicals affecting adrenal function appear to do so by altering steroidogenesis. A study of the effects of these chemicals on the histology and ultrastructure of adrenal cortical cells often can give insight into possible selection sites of inhibition of steroidogenesis. For example, chemicals causing increased lipid droplets may be involved in inhibiting the utilization of steroid precursors, including the conversion of cholesterol to pregnenolone. Chemicals that affect the fine structure of mitochondria and smooth endoplasmic reticulum would be expected to impair the activity of 11α-hydroxylase and 17α- and 2l-hydroxylases, respectively. The previously mentioned examples of impaired steroidogenesis would result in lesions found primarily in the ZR and ZF. However, atrophy of the ZG may reflect specific inhibition of aldosterone synthesis or secretion, either directly (inhibition of 18Q1-hydroxylation) or indirectly (inactivation of the renin–angiotensin system II), by chemicals such as spironolactone and captopril, respectively. The inhibition of steroidogenesis in some situations is nonspecific, as many hydroxylation reactions are affected, such as with carbon tetrachloride and cadmium intoxications.

Abstract

The endocrine system is essential for the growth and development of the fetus. Development of the fetal endocrine system commences early in gestation allowing hormones to regulate functions in various physiological systems preparing the fetus for postnatal life. Hormone bioavailability in utero depends on both the formation of the endocrine gland for its production and the maturation of the responsiveness of the target tissue. Key features surrounding these events are presented for endocrine actions affecting fetal growth rates because appropriate growth is an essential component in a successful outcome of pregnancy. Furthermore, adaptations in fetal endocrinology are important factors that respond to a variety of clinically relevant complications in pregnancy that cause intrauterine growth. In this article, we discuss animal models of fetal endocrinology to explain the role hormones play in modulating fetal growth, development, and metabolic homeostasis.

Introduction: Overview of the Endocrine System

The endocrine system is one of the most important regulators of homeostasis within the human body. The endocrine system releases hormones (signaling molecules) into the bloodstream to impart biological effects in other organs or tissues in response to disruptions in homeostasis [1]. Paracrines, also called local hormones, are secreted by one cell to other cells within the same tissue [2]. These hormones are synthesized in the endocrine glands, the most important of which are the pituitary gland, adrenal glands, thyroid gland, parathyroid gland, pineal gland, and hypothalamus [2]. These endocrine glands are located throughout the body and, due to the direct deposition of hormones into the circulatory system, can enact responses in both proximal and distal areas of the body [1]. Many organs, such as the gonads, pancreas, liver, heart, and kidney, which are not primary endocrine constituents, also play roles in hormone response pathways [3].

In humans, many endocrine system responses are controlled along the hypothalamic–anterior pituitary–peripheral axis [1]. The hypothalamus gland in the lower brain secretes hormone signals to the anterior lobe of the pituitary gland located beneath it. In response to these hypothalamic signals, the anterior lobe of the pituitary gland produces and secretes a number of different hormones that regulate metabolic processes and/or further signal responses in other endocrine glands [1].

Abstract

The immune and endocrine systems collectively control homeostasis in the body. The endocrine system ensures that values of essential factors and nutrients such as glucose, electrolytes and vitamins are maintained within threshold values. The immune system resolves local disruptions in tissue homeostasis, caused by pathogens or malfunctioning cells. The immediate goals of these two systems do not always align. The immune system benefits from optimal access to nutrients for itself and restriction of nutrient availability to all other organs to limit pathogen replication. The endocrine system aims to ensure optimal nutrient access for all organs, limited only by the nutrients stores that the body has available. The actual state of homeostatic parameters such as blood glucose levels represents a careful balance based on regulatory signals from the immune and endocrine systems. This state is not static but continuously adjusted in response to changes in the current metabolic needs of the body, the amount of resources it has available and the level of threats it encounters. This balance is maintained by the ability of the immune and endocrine systems to interact and co-regulate systemic metabolism. In context of metabolic disease, this system is disrupted, which impairs functionality of both systems. The failure of the endocrine system to retain levels of nutrients such as glucose within threshold values impairs functionality of the immune system. In addition, metabolic stress of organs in context of obesity is perceived by the immune system as a disruption in local homeostasis, which it tries to resolve by the excretion of factors which further disrupt normal metabolic control. In this chapter, we will discuss how the immune and endocrine systems interact under homeostatic conditions and during infection with a focus on blood glucose regulation. In addition, we will discuss how this system fails in the context of metabolic disease.

The Concept of Control